In the healthy nervous system, the development of intention and motor execution is a dynamic and highly distributed process that originates in the brain. The intended action is transmitted along the axonal super highway to smart circuits in the spinal cord that transform the descending command into coordinated patterns of muscle activation. While much is understood regarding the control strategies the brain uses to drive upper limb movements, relatively little is known about the central control of human locomotion. Further, failures of function in one seemingly insignificant processing loop in the brain or periphery can, and often does, lead to dramatic consequences that induce transient or permanent deficits in motor control. A particularly palpable example of this is the consequences resulting from spinal cord injury (SCI), which, in extreme cases, can render a person completely unable to interact with the world around them. Such nervous system injuries and disorders have long-term health, economic and social consequences in both the civilian and Veteran population. Despite the best available medical treatments, hundreds of thousands of individuals endure a long life post-SCI with sensorimotor deficits that dramatically affect their quality of life. The specific objective of this project is to build fundamental knowledge of how motor cortex (MI) controls voluntary, as well as stereotypic, lower limb movements, and then to design both a brain-spine interface leveraging a fully implanted hardware system, as well as a first of its kind end-point brain-machine interface for lower limb prosthetics. We will study the basic function of nonhuman primate motor cortices during a variety of hind limb movements, including passive walking on a treadmill, during obstacle avoidance, and direct endpoint control on a sitting flywheel while recording high-fidelity neural population data and kinematics. Finally, our results will be interpreted in the context of supporting a translational clinical study in humans to provide a new rehabilitation pathway for Veterans with spinal injury, as well as neuroprosthetic pathway for amputees. We will conclusively determine the strategies employed by nonhuman primate motor cortex to both drive and adjust hind limb placement during locomotion and we will determine if motor cortex activity consequently changes between so-called ?automatic? movements (e.g. walking on a treadmill), and volitional, highly precise movements (e.g. end-point control on a flywheel). The proposed study will work with rhesus monkeys trained to walk on an instrumented treadmill, across a flat corridor, freely within a large naturalistic roaming space, as well as controlling the pedal location along a 2- dimensional flywheel. Animals will be implanted with a) two silicon microelectrode arrays in MI-leg, and premotor area (PMd) containing movement planning information; b) an implantable pulse generator connected to a custom epidural spinal cord stimulation microelectrode array; and c) electromyography sensors in key gait muscles of the lower limb. Animals will be evaluated across all locomotor contexts, as well as in their customized home-cage, using wireless data transmission. We will evaluate the long-term use of the BSI both to restore functional locomotion, and to support other daily nonhuman primate activities. Finally, we will leverage the knowledge gained about the motor cortex?s role in locomotion, as well as our previous development of a brain-spinal interface, to deploy a fully-implanted brain-spinal interface for human translation within the VA for application to veteran locomotor rehabilitation.